Targeting citrullination in autoimmunity: insights learned from preclinical mouse models

ABSTRACT

Introduction

Aberrant citrullination and excessive peptidylarginine deiminase (PAD) activity are detected in numerous challenging autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes. Because excessive PAD activity is a common denominator in these diseases, PADs are interesting potential therapeutic targets for future therapies.

Areas covered

This review summarizes the advances made in the design of PAD inhibitors, their utilization and therapeutic potential in preclinical mouse models of autoimmunity. Relevant literature encompasses studies from 1994 to 2021 that are available on PubMed.gov.

Expert opinion

Pan-PAD inhibition is a promising therapeutic strategy for autoimmune diseases. Drugs achieving pan-PAD inhibition were capable of ameliorating, reversing, and preventing clinical symptoms in preclinical mouse models. However, the implications for PADs in key biological processes potentially present a high risk for clinical complications and could hamper the translation of PAD inhibitors to the clinic. We envisage that PAD isozyme-specific inhibitors will improve the understanding the role of PAD isozymes in disease pathology, reduce the risk of side-effects and enhance prospects for future clinical translation.

KEYWORDS:

• Autoimmune disease
• citrullination
• immunomodulation
• PAD isozyme-specific inhibitors
• pan-PAD inhibitors
• peptidylarginine deiminases
• preclinical mouse models
• therapeutic targets
• drug targets

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

One reviewer is a consultant for several companies who are developing PAD inhibitors for human use. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Article highlights

• Autoimmune diseases are complex and heterogeneous, with current treatment often focused on symptom alleviation and immune suppression rather than on causal or preventative interventions/measures.

• Aberrant citrullination and peptidylarginine deiminase (PAD) activity are common denominators in disease onset and progression in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), multiple sclerosis (MS) and type 1 diabetes (T1D).

• PADs are potent therapeutic targets in autoimmune diseases by repressing, reversing and preventing clinical symptoms, as evidenced by murine models.

• Pan-PAD inhibition is effective in autoimmune diseases due to various immunomodulatory and tissue-specific effects.

• The generation of isozyme-specific inhibitors will aid our understanding of the isozyme-specific role in normal physiology and disease pathology. These inhibitors may also reduce the risk of unwanted side effects expected with pan-PAD inhibitors.

This box summarizes key points contained in the article.

Additional information

Funding

Related work in the author's laboratory (CM and LO) is funded by IMI2-JU under grant agreement No 115797 (INNODIA) and No 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the Union’s Horizon 2020 research and innovation program and “EFPIA”, “JDRF” and “The Leona M. and Harry B. Helmsley Charitable Trust”. Funding was also obtained from the KU Leuven (C16/18/006). YB is funded by a predoctoral fellowship from the Flemish Research Foundation (1179921N).